Racemization of an alpha-methyl dopa derivative

ABSTRACT

A process for racemizing an optically active isomer of an amidoester in a lower alkanol by the use of ammonia which causes trace equilibration.

United States Patent Hinkley et al. July 1 1, 1972 [54] RACEMIZATION OFAN ALPHA- [56] References Cited METHYL DOPA DERIVATIVE FOREIGN PATENTSOR APPLICATIONS [72] Inventors: David F. Hinkley, Plainfield; Robert L.Ell- 1,372,199 8/1964 France sworth, Basking Ridge, both of NJ. [73]Assignee: Merck 8: Co., Inc., Rahway, NJ. OTHER PUBLICATIONS 22] Filed:March 14 1969 Elie]. Stereochem. of Carbon Cmps. p. 35 QD48 I E5.

[2]] App]. No.: 839,739 Primary Examiner-Lorraine A. Weinberger RehtedApplication Data Assistant ExaminerL. Arnold Thaxton Attorney-John P.Floyd, Harry E. Westlake, Jr. and 1. Louis [62] DIvIsIon of Ser. No.502,355, Oct. 22, 1965, abanw doned.

52 us. Cl ..260/471 II, 260/465 D, 260/519 [57] ABSTRACT Int- u I ..C07cA process for racemizing an optically active isomer of an [58] Field ofSearch ..260/519, 470, 465

amidoester in a lower alkanol by the use of ammonia which causes traceequilibration.

1 Claim, No Drawings RACEMIZATION OF AN ALPHA-METHYL DOPA DERIVATIVEThis application is a division of U.S. Ser. No. 502,355 filed Oct. 22,1965, now abandoned.

This invention relates to a new process for obtaining the op ticalisomers of a phenyl-substituted a-methyl-acyanopropionic acid and itsesters, important intermediates in the production of certain opticallyactive a-methylphenylalanines. More particularly, this invention relatesto a process for preparing the foregoing cyano esters, resolving theracemates to give the desired enantiomorph in substantially pure form,and racemizing the unwanted enantiomorph for recycle.

a-Methyl-B-(3,4-dihydroxyphenyl)alanine, or a-methyl- DOPA as it isusually called, has been demonstrated to be a potent antihypertensiveagent in man. The 4-hydroxy analog, commonly called a-methyltyrosine, isa promising tranquilizer. The activity of these compounds is in theL-form. The D- forms are completely inactive as antihypertensive ortranquilizing agents, but are equally as toxic as the L-form. It istherefore important to obtain the L-form, free of the D-form for use inmedicine.

Exemplary of the manner in which L-hydroxyphenyl-aalkyl-alanines arepresently produced is the preparation of amethylDOPA. The synthesis ofthis compound usually proceeds from methyl vanillyl or veratryl ketoneis one of two ways. Either the ketone is reacted with ammonium carbonateand a cyanide salt to form a hydantoin, which upon hydrolysis deliversthe corresponding a-methyl methoxy hydroxy (or dimethoxy) phenylalanine,or the ketone is reacted with ammonium cyanide to form ana-amino-a-vanillyl (or veratryl) propionitrile, which can be hydrolyzedstepwise to the corresponding amide and then simultaneously demethylatedand hydrolyzed to form the dihydroxyphenyl-alanine. These prior methodsgenerally resolve the optical isomers at the end of the synthesis, or atan intermediate stage in assembling the molecule.

However, such procedures result in an accumulation of unusable D-form,which cannot be readily racemized or economically degraded to anintermediate which can be reused, or they result in processingcomplications at an intermediate stage where the usual losses ofseparation and racemization consume expensive intermediates.Consequently, there continues to be a need for a more economicalcommercial synthesis.

The primary object of this invention is to provide an optically activeintermediate which can simply and economically be converted to thedesired optically active a-methyl-phenylalanines. A further object is toprovide a unique method for the synthesis and resolution of suchintermediates. Another object is to provide a process for the synthesisof the cyano ester intermediates of this invention which employsreagents that are simply and cheaply produced from readily available rawmaterials. These and other objects of this invention will appear morefully hereinafter.

ln accordance with this invention, the a-methyl-acyanophenylalanines andesters of this invention, in the desired optically active form, areproduced by a process which comprises l contacting a compound having theformula:

wherein R and R can be the same or different and are hydrogen orlower-alkyl, n is or 1, and X is halo, or diloweralkylamino, with alower -alkyl ester of a-cyanopropionic acid and concomitantly removinghydrogen halide (for example, by using a suitable amount of base) toproduce a compound having the formula wherein R,, R,, and n are asdefined above and R, is lower alkyl, (2) hydrolyzing said lower-alkylester to produce a compound having the formula;

an amido ester having the formula:

CH; (1110).,- Cllz-C-COHK R20 C 0 NH:

in the D configuration wherein R R R and n are as defined above, (5)racemizing said D amido ester to produce a racemic mixture of D and Lisomers of said amido ester and (6) containing said racemic mixture witha dehydrating agent to produce the corresponding compound wherein theamide function is reconverted to the original nitrile function. Thepreparation of a-methyl-a-cyano-B-(3,4-di-lower-alkoxyphenyl)propionicacid ester which comprises contacting a 3,4-dialkoxybenzyl halide with alower-alkylester of a-cyanopropionic acid to produce a lower-alkylesterof a-cyano-amethyl-B-(3,4-dialkoxyphenyl)propionic acid, contacting saidester with an aqueous solution of a strong acid to hydrolyze said esterand produce the corresponding free acid as a racemic mixture of D and Lisomers, resolving said racemic mixture and recovering the L isomerthereof and recycling the D isomer by a process of l hydrolysis of thecyano group to a carbamoyl group, (2) racemizing the resulting amide bycontact with a small amount of a base (generally a strong base), and (3)dehydrating the resulting racemate to produce the lower-alkyl ester ofa-cyano-a-methyl-B-(3,4-dialkoxyphenyl)propionic acid as a racemicmixture is a preferred embodiment of this invention. Another preferredembodiment is the foregoing embodiment, wherein a 4-alkoxy-benzylhalideis employed to produce the corresponding cyanoester, i.e., thelower-alkyl ester of a-cyano-a-methyl-B-(4-alkoxyphenyl)propionic acid.

The following examples more fully demonstrate this invention.

EXAMPLE I A. 3,4-Dimethoxybenzylchloride To a solution of 138 g. (1.0mole) veratrole in 500 ml. of benzene saturated with hydrogen chlorideat l0 C. is added 37.6 g. (0.42 mole) of paraformaldehyde [(HCl-lO);,].The slurry is then stirred at 10 C. rising to 40 C. while hydrogenchloride is bubbled through for min. The solution is filtered andconcentrated under reduced pressure to a residual oil which isfractioned at ll5l l8ll mm. to give a distillate solidifying to a whitesolid, 3,4-dimethoxy-benzylchloride.

B. 4-Methoxybenzylchloride To a solution of 108 g. (1.0 mole) ofmethoxy-benzene in 500 ml. of benzene saturated with hydrogen chlorideat 10 C. is added 37.6 g. 0.42 mole) of paraformaldehyde [(HCHOM Theslurry is then stirred at 10 C. rising to 40 C. while hydrogen chlorideis bubbled through for 90 min. The solution is filtered and concentratedunder reduced pressure to a residual oil which is fractionated to give adistillate solidifying to a white solid, 4-methoxy-benzylchloride.

EXAMPLE II A. Preparation Of The Methyl Ester 0f a-methyl-a-cyano-fl(3,4-dimethoxyphenyl)propionic acid To a solution of sodium methoxideprepared from 11.5 g. (0.5 mole) of sodium in 400 ml. of dry methanol isadded a solution of 56.5 g. (0.5 mole) of methyl ester ofacyanopropionic acid in 60 ml. of methanol over one hour at 25 C. Tothis solution of the cyanoester enolate is added a solution of 93.3 g.(0.5 mole) of 3,4-dimethoxybenzyl chloride in 100 ml. of methanol over30 min. and the resulting mixture is heated to reflux for four hours.The mixture is cooled, the salt removed by filtration, and the filtrateconcentrated under reduced pressure to a residual oil which, uponaddition of 200 ml. of hexane, crystallizes on cooling, giving a goodyield of the product, the methyl ester of a-methyl-a-cyano-B-(3,4-dimethoxyphenyl)propionic acid.

Preparation Of The Methyl Ester Of a-methyl-a-cyano-B-(4-methoxyphenyl)propionic acid The procedure of Example ll(B) isfollowed, with the exception that 0.5 mole of 4-methoxybenzyl chlorideis employed in place of 0.5 mole of 3,4-dimethoxybenzyl chloride, toproduce the corresponding methyl ester ofa-methyl-acyano-B-(4-methoxyphenyl)propionic acid.

The procedure of Example 11 is repeated, using the ethoxy, n-propoxy,i-propoxy, n-butoxy, t-butoxy, and the like alkoxy analogs of4-methoxybenzyl chloride, in equivalent molar amounts, to produce,respectively, the methyl ester ofamethyl-a-cyano-B-(4-ethoxyphenyl)propionic acid;a-methyla-cyano-B-(4-n-propoxyphenyl)propionic acid;a-methyl-acyano-B-(4-i-propoxyphenyl)propionic acid;a-methyl-acyano-B-(4-n-butoxyphenyl)propionic acid;a-methyl-acyano-B-(4-t-butoxyphenyl)propionic acid. Likewise, varioushydrocarbyl esters can be produced, using the procedures of Example 11,by substituting for the methyl-a-cyano propionate employed therein, thecorresponding ethyl, i-propyl, n-butyl, hexyl, octyl, and the likea-cyano propionates, to produce the corresponding alkyl esterderivatives.

The preparation of thea-lower-alkyl-a-cyano-B-(p-alkoxylatedphenyl)propionic acid estersinvolves a nucleophilic displacement which can be effected by utilizinga labile leaving function other than halide. For example, in place ofthe p-alkoxybenzyl halide, the tosyl or mesyl derivatives of thecorresponding benzyl alcohol may be employed. Preparation of thecorresponding p-hydroxy compounds, however, proceeds viaeliminiation-addition (on the intermediate quinone methide), and notonly all the above leaving groups may be employed, but also theN-di-lower-alkyl derivative, for example, N-dimethyl vanillyl amine.Furthermore, other alkali metals and alkanols can be employed in placeof the sodium and methanol in Example 11, depending upon whatlower-alkyl ester is desired. Exemplary of the alkali metals arepotassium, lithium, rubidium, and cesium, and the alcohols ethanol,propanol, butanol, and the like can be employed.

In carrying out these nucleophilic displacements, since the reactionproceeds on a stoichiometric basis, it is generally preferred to employstoichiometric amounts of all reactants. However, the p-hydroxybenzylamine compounds react on an auto-catalytic basis and in the latter case,it is preferred to employ from about 5 to about percent of the alkalimetal alkoxide, (i.e. 0.05-0.l:1 of said alkoxide to the foregoingmentioned dialkylamine.

It should be noted, that in addition to the alkali metal alkoxides,other enolyzing agents can be employed, such as alkali metal hydrides,for example, sodium hydride, potassium hydride, and lithium hydride;alkali metal sands or dispersions, such as potassium or lithium sanddispersions, or other conventional enolyzing agents.

In general, the temperature of the nucleophilic displacement step ofthis invention does not appear to be critical and can be conducted at atemperature sufficient to initiate the reaction, but below thedecomposition temperature of the reactants and products. In mostinstances, this temperature falls within the range from about 25 C. toabout 100 C. Any inert solvent, that is any solvent which will notinterfere with the desired reaction, can be employed, as, for example,benzene and other inert aromatic hydrocarbon solvents, hexane, and thelike inert aliphatic carbon solvents, inert ethers such astetrahydrofuran, and the like inert solvents.

EXAMPLE 111 Resolution Of Cyanoester to a solution of 87.7 g. (0.33mole) of the methyl ester ofDL-a-methy1-a-cyano-B-(3,4-dimethoxyphenyl)propionic acid in 300 ml. offive percent aq. acetone is added 1.0 ml. of cone. sulfuric acid understirring at 25 C. After one hour the solution is added to a column of250 g. (0.63 mole) of brucine thoroughly admixed with 250 g. ofSupercel. The filled column is allowed to equilibrate for two hours andis then eluted with 400 ml. of acetone-petroleum ether (1:3) at a rateof 40 ml./hr. The fraction containing the soluble brucine salt of theL-cyanoacid is concentrated and dissolved in slightly acidifiedmethanol, which gives on reconcentration, a precipitate of methyl esterof L-a-methyl-a-cyano-B-(3,4- dimethoxyphenyl)propionic acid.

Leaching of the column with neat acetone gives the lesssoluble brucinesalt which on similar work up yields the D- cyanoester, the methyl esterof D-a-methyl-a-cyano-B(3,4- dimethoxyphenyl)propionic acid.

Similarly, the resolution of the methyl ester ofD,L-amethyl-a-cyano-B-(4-methoxyphenyl)propionic acid can be effected bysubstituting this racemic compound for the dimethoxy derivative employedin Example Ill.

The resolution illustrated by the foregoing examples can be carried outusing other optically active bases as a resolving agent, as for example,cinchonine, cinchonidine, quinine, quinidine, strychnine, morphine,l-menthylamine, dand l-aphenylethylamine, d-Z-amino-l-hydroxyhydrindene,L-arginine and a-methylbenzyl amine. Although in the foregoing examples,the resolution is effected by producing a salt of the free acid,resolution can be effected via a free phenolic function, using theforegoing resolving agents. For example, the 4- hydroxyphenyl analogscan be resolved in this fashion.

In addition to the inverse resolving technique employed in Example III,which involves recovery of the less soluble salt after elution of theother salt, the more conventional batch selective crystallizationtechnique, yielding the less soluble salt directly can also be utilized.

EXAMPLE lV Preparation Of Amidoester One mole (263 g.) of the methylester of D-a-methyl-acyano-B-(3,4-dimethoxyphenyl)propionic acid isdissolved in 2 kg. of percent sulfuric acid and heated under stirring at-l 10 C. for 12-15 hours. The solution is cooled, poured slowly intocracked ice under stirring and then extracted 3 X 333 ml. of methylenechloride. The combined extracts are washed with dilute bicarbonate,dried and concentrated in vacuo to a yellow gum. The residue is digestedwith 3 X 500 ml. of methanol and then reconcentrated to low volume (300ml.) in vacuo to give a heavy slurry, which on cooling over ice yields259 g. (0.92 mole) of the methyl ester ofD-a-methyl-acarbamoyl-B-(3,4-dimethoxy-phenyl)propionic acid.

When the foregoing Example IV is repeated utilizing the 4- methoxyhomolog, the corresponding methyl ester ofD-amethyl-a-carbamoyl-B-(4-methoxyphenyl)propionic acid is prepared.

The foregoing hydrolysis of the cyanoester to the amidoester (the termsamido" and carbamoyl are interchangeably used herein) can be carried outusing other hydrolysis techniques. For example, in addition to thesulfuric acid employed in the foregoing example, other mineral acids canbe employed, as for example, dilute hydrochloric acid. Still anotherprocedure for converting the cyanoester into the corresponding amideinvolves the use of sulfuric acid monohydrate. Hydrogen peroxide canalso be employed, using alkaline conditions. Another procedure comprisesheating the cyanoester with polyphosphoric acid. Conversion of thenitrile function of the cyanoester to the amidoester can also involvethe use of methanolic hydrogen chloride to produce the correspondingiminoether, followed by pyrolysis to the desired amidoester.

EXAMPLE V Racemization Of The D-Amidoester To 1 l. of xylene containing1.0 g. (0.0184 mole) of sodium methylate is added ml. of methanolcontaining 0.16 g.

(0.0092 mole) of ammonia and 259 g. (0.092 mole) of the methyl ester ofD-a-methyLa-carbamoyl-B-(3,4-dimethoxyphenyl)propionic acid in a stirredautoclave. The mixture is heated under stirring for 4 hours at 170 andthen cooled and washed with cold 0.1 N hydrochloric acid. The xylenelayer is then concentrated in vacuo to low volume, diluted with l 1. ofmethanol and reconcentrated in vacuo to about 300 ml. to give a heavyslurry, which on cooling over ice, gives good yields of the methyl esterof DL-a-methyl-a-(3,4-dimethoxyphenyl)propionic acid.

Similarly, the other optically active arnido alkyl esters can be soracemized, as for example, the ethyl, propyl, butyl esters, andcorresponding branch chain derivatives thereof, as well as monoanddialkoxy analogs of the D-amidoester starting material used in ExampleV, such as 3,4-diethoxy, 3,4- dipropoxy, 3,4-dibutoxy, 4-methoxy,4ethoxy, 4-propoxy, 4- butoxy, and the like to produce the correspondingalkyl esters of an a-methyl-a-carbamoyl-B-(alkoxylatedphenyl)propionicacid.

The foregoing example demonstrates the racemization of the unwantedoptically active isomer for recycle in the process of this invention. Itshould be noted that this racemization employs a novel traceequilibration principle to convert the asymmetric carbon of theD-amidoester to its optically inactive or racemized form via traceequilibration with the nonasymmetric diamide. This is therefore apreferred embodiment of this invention, since it provides an extremelysimple, straight-forward and economical racemization technique,

which has broad potential applicability to a number of other opticallyactive systems where there is comparable equilibria as for example, thereversible hydrolysis-dehydration of an asymmetric geminal cyanamide tothe symmetrical diamide in the presence of a large volume of phosphorusacid.

EXAMPLE VI Preparation of the DL-cyanoester from the correspondingDL-Amidoester The 228 g. (0.81 mole) of the DL-amidoester, dissolved in500 ml. of sym.tetrachloroethane is added 300 g. of Supercel and 173 g.(1.22 moles) of phosphorus pentoxide. The mixture is refluxed understirring for five hours, cooled and quenched into 1.5 l. of water. TheSupercel is removed by filtration and the filtrate layers separated. Theorganic layer is concentrated in vacuo to low volume, flushed 3 X 500ml. of hexane in vacuo and finally reconcentrated to a residual volumeof 350 ml. Cooling to 0-5 C. for two hours gives 168.5 g. (0.64 mole),if the methyl ester ofDL-a-methyl-acyano-B-(3,4-dimethoxyphenyl)propionic acid.

The procedure of Example VI can also be employed in the conversion ofthe methyl ester DL-a-methyl-a-carbamoyl-B- (4-methoxyphenyl)propionicacid to the corresponding cyanoester.

The foregoing DL cyanoester is suitable for recycle to the resolutionstep, for example, that described in Example 111 above. It can thereforebe seen that this invention provides an excellent method for utilizingthe unwanted optical isomer in the preparation of the commerciallyimportant enantiomorph.

For example, in the foregoing series of examples, the L form of themethyl ester of a-methyl-a-cyano-fl-(S,4-dimethoxyphenyl)propionic acidis suitable for conversion to the therapeutically important hypotensiveagent, L-a-methyl- DOPA, since the L form of the cyanoester intermediateis rendered free of the D form with out concomitant accumulation ofunusable D form.

In addrtron to the dehydration procedure set forth in Example Vl, whichemploys phosphorus pentoxide, other reagent techniques can be utilized,for example, the dehydration can be carried out by utilizing halides oranhydrides of organic or inorganic acids in the presence of heat, orutilizing catalytic methods (see Chemical Reviews, 42, 189). Exemplaryof inorganic halides, are phosphorus pentachloride, phosphorusoxychloride, thionyl chloride. Exemplary of acid anhydrides which can beemployed are acetic anhydride, succinic anhydride, and the like. Byutilizing the foregoing dehydration agents, a wide range of theoptically active amidoesters of this invention can be converted to thecorresponding racemic amidoesters. For example, the ethyl, propyl andbutyl esters of the a-methyl-a-earbamoyl-B-(3,4-dimethoxyphenyl)-propionic acid, or such esters of the a-methyl-a-carbamoyl-B-(4-methoxyphenyl)propionic acid can be converted to the correspondingcyanoesters, utilizing the above-described dehydration agents. Likewise,other alkoxylated phenyl analogs can be so converted, as for example,the ethoxy, propoxy, butoxy, monoand di-substituted analogs of suchamethyl-a-arnido-(alkoxylatedphenyl)propionic acid esters.

When Examples V and V] are repeated using equal proportions of otheroptically active amidoesters, in place of the methyl ester ofa-methyl-a-methyl-carbamoyl-B-(3,4- dimethoxy-phenyl)propionic acidemployed therein, similar yields of the desired racemate are obtained.For example, the methyl ester ofD-a-methyl-a-carbamoyl-B-(4-methoxyphenyl propionic acid gives themethyl ester of D,L-a-methyl-acyano-B-(4-methoxyphenyl)propionic acid;ethyl ester of D- a-methyl-a-carbamoyl-B-(3,4-diethoxyphenyl)propionicacid gives the ethyl ester ofD,L-a-methyl-a-cyano-B-(3,4-diethoxyphenyl)-propionic acid; the i-propylester of D-a-methyl-acarbamoyl-B-(3,4-di-n-butoxyphenyl)propionic acid;gives the i-propyl ester ofD,L-a-methyl-a-cyano-B-(3,4-di-n-butoxyphenyl)-propionic acid; thesec-butyl ester ofD-a-methyl-acarbamoyl-B-(3,4-di-n-butoxyphenyl)propionic acid gives thesec-butyl ester ofD,L-a-methyl-a-cyano-B-(3,4-di-n-butoxyphenyl)propionic acid; andsimilarly, other alkyl esters of an optically activea-methyl-a-carbamoyl-B-(alkoxylated-phenyl)propionic acid give thecorresponding ester of aD,L-amethyl-a-cyano-fi-(alkoxylatedphenyl)propionic acid. In general,the D-enantiomorph is employed in preparation of the racemate, since itis the 1. form which exhibits the desired end-use properties, as hasbeen discussed above. Thus, it is the D-form which is available forracemization and recycle in the process of this invention.

What is claimed is: 1. The process which comprises contacting theD-optically active isomer of an amidoester having the formula (I311;(1310);- CH2(|3CO2R3 C ONHz Egowherein R R and R,, can be the same ordifferent and are lower alkyl, and n is 0 or 1, with a minor amount ofammonia and a strong base and a substantial excess amount of R saidamounts being sufficient to effect racemization.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO.3,676,482 DATED July 11, 1972 INVENTOR(S) David F. Hinkley et al.

It is certified that error appears in the ab0ve-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 25 After "ketone" delete [is] and insert in its place i11.

Column 1, second structural formula (R 0) should read II II n Column 2,line 26 After (6) delete [containing] and insert in its placecontacting.

Column 2, line 61 After "which is" delete [fractioned] and insert in itsplace fractionated. I

Column 3, line 14 "preparation".

Insert "B. before the word Column 5, line 18 After the second "0."insert "6-".

Column 5, line 57 After"mole) delete [if] and insert in its place o fColumn 6, line 31.

Delete the third "methyl" in the line.

Column 6, Claim 1, line 65 Delete [R and insert in its place R OH.

Signed and Scaled this thirtieth Day of Dtttttttbtt 1975 [SEAL] Arrest:

RUTH C. MASQN C. MARSHALL DAN" AM -fli g Office (omminitmrr a] Putin:and Trademarks

